Recurrent Pregnancy Loss What can we do? · Recurrent Pregnancy Loss | Recurrent Pregnancy Loss...

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Recurrent Pregnancy Loss What can we do?

Pradnya Pisal London Gynaecology

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Recurrent Pregnancy Loss

03/06/16

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Defn:RecurrentPregnancyLoss(RPL)

•  Classical:3ormoreconsecu>vepregnancylossesbefore20weeksgesta>on,1-2%

•  5% couples experience 2/> consecutive losses

•  Riskoffurtherpregnancylossissimilarfor2and3consecu>velosses,43.7%,44.6%

•  Inves>ga>onmaybeappropriateaNer2pregnancylosses,especiallyinolderwomenandifkeentobeinves>gated

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RecurrentPregnancyloss

•  Possiblecauses

•  Inves>ga>on

•  Management

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Causes

•  Age•  Previouspregnancyloss•  Uterinefactors

•  Anomalies•  Fibroids•  Polyps•  Adhesions•  Cervicalinsufficiency•  Defec>veendometrialrecep>vity

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Causes

•  Immunologicalfactors•  An>phospholipidsyndrome•  Otherimmunologicalfactors

•  Endocrinefactors•  Diabetesmellitus•  PCOS•  Thyroidan>bodiesanddisease•  Hyperprolac>naemia•  Lutealphasedefects

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Causes

•  Chromosomalabnormality•  Gene>cdisorders•  Thrombophilia •  Infec>on•  Decreasedovarianreserve•  Personalhabits•  Malefactor•  Environmentalchemicalsandstress

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Age

12-19yrs 13% 20-24yrs: 11% 25-29yrs: 12% 30-34yrs: 15% 35-39yrs: 25% 40-44yrs: 51% >/=45yrs: 93%

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Chromosomalabnormality

%Abnormal Gesta/onalage

60 12

45 16

12 20

6 24

-1 40

•  Increaseswithadvancingmaternalage•  Parentalabnormali>esin3-5%ofcoupleswithRPL•  Balancedtransloca>onmostcommon

•  Reciprocal(60%)orRobertsonian(40%)•  25-50%riskofpregnancyloss

•  Trisomy,monosomyandtriploidy;85%losses

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Karyotyping

•  Shouldbeperformedonproductsofconcep>on(POC)ofthe3rdandsubsequentconsecu>vemiscarriage(s)

•  ParentalperipheralbloodkaryotypingofbothpartnersshouldbeperformedincoupleswithRPLwheretes>ngofPOCreportsanunbalancedstructuralchromosomalabnormality,orPOCarenotavailableforkaryotyping

•  Ifthekaryotypeofthemiscarriedpregnancyisabnormal,thereisabe`erprognosisforthenextpregnancy

•  RoleforPGDinIVFpregnancies

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An>phospholipidsyndrome(APS):Hughessyndrome

•  Mostimportanttreatablecauseofrecurrentmiscarriage,2%innormal,15%withRPL.

•  Associa>onbetweenan>phospholipidan>bodies–lupusan>coagulant,an>cardiolipinan>bodiesandan>-B2glycoprotein-Ian>bodies–andadversepregnancyoutcomeorvascularthrombosis.

•  Test:on2ormoreoccasionsatleast12weeksapart

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APS:Adversepregnancyoutcomes

•  Threeormoreconsecu>vemiscarriagesbefore10weeksofgesta>on

•  OneormoremorphologicallynormalfetallossesaNerthe10thweekofgesta>on

•  Oneormorepretermbirthsbeforethe34thweekofgesta>onowingtoplacentaldisease.

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APSan>bodies:ac>on

•  Inhibi>onoftrophoblas>cfunc>onanddifferen>a>on•  ac>va>onofcomplementpathwaysatthematernal–fetalinterfaceresul>nginalocalinflammatoryresponse

•  inlaterpregnancy,thrombosisoftheuteroplacentalvasculature

•  InvitrostudieshaveshownthattheeffectofAPSan>bodiesontrophoblastfunc>onandcomplementac>va>onisreversedbyheparin.

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Treatment

•  Stronglyadvisewomentoplanpregnancy•  Stopsmoking•  Maintaingooddietandhealthyweight•  Regularexercise•  Aspirin•  Clexane

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Cervicalincompetence

•  Lookforhistory:LargeLLETZ,conebiopsy,transcervicalmyomectomy,later1stTMTOPorERPC,painless2ndTMlossorPPROM

•  Currentlynosa>sfactoryobjec>vetestthatcaniden>fywomenwithcervicalweaknessinthenon-pregnantstate

•  Inwomenwithsingletonpregnancy&one2ndTMmiscarriagea`ributabletocervicalfactors,anUSS-indicatedcerclage,ifcervicallengthof</=25mmisdetectedbyTVSbefore24wks

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Normalcervix Shortcervix

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Management:cervicalincompetence

•  Serialcervicallengths•  Progesteronesupport•  Prophylac>ccervicalsuture

•  Vaginal:•  MacDonald’s•  Shirodkar’s

•  Abdominal•  Laparoscopic•  Open

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Uterineanomalies

•  Prevalence&implica>onsingeneralisunknown•  InRPL:between1.8%and37.6%•  RPLmayberelatedtocervicalincompetence•  Higherprevalencewith2ndTMlosscomparedwith1stTMmiscarriages,PTD•  Termdeliveryrateofonly50%

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Uterineanomalies:Treatment

•  Stronghistory•  PelvicUSS,3DUSS,MRI•  Hysteroscopicevalua>on+/-laparoscopy•  Transcervicalresec>onofseptae•  Hysteroscopicresec>onof:

•  polyps•  fibroids•  adhesions

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Endocrinefactors:DM

•  PoorlycontrolledDiabetesmellitushasbeenassociatedwithmiscarriage

•  WomenwithdiabeteswhohavehighhaemoglobinA1clevelsinthe1stTMareatriskofmiscarriageandfetalmalforma>on

•  Pre-pregnancycounseling:Improvediet,exercise,bloodglucosecontrol,5mgfolicacidpriortopregnancy

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Endocrinefactors:Thyroiddisease

•  Thyroiddysfunc>on&An>-thyroidan>bodieshavebeenlinkedtorecurrentmiscarriage

•  TSH:4-5mIU/LwasconsiderednormalbutrecentlyTSHvalueofover2.5mIU/Lareconsideredoutsidenormalrange

•  Hencelookforandtreatsubclinicalhypothyroidism

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Polycys>covariansyndrome:PCOS

•  Increasedriskofmiscarriagerecentlya`ributedtoinsulinresistance,hyperinsulinaemia,hyperandrogenaemiabutuncertaincause(?highLHlevels)

•  Elevatedfreeandrogenindexappearstobeaprognos>cfactorforasubsequentmiscarriageinwomenwithrecurrentmiscarriage

•  Treatment:Diet,Exercise,Meqormin,Progesteronesupport

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Immunefactors

•  Noclearevidencetosupporthumanleucocytean>genincompa>bilitybetweencouples,theabsenceofmaternalleucocytotoxican>bodiesortheabsenceofmaternalblockingan>bodies

•  Naturalkiller(NK)cellsarefoundinperipheralbloodandtheuterinemucosa

•  NoclearevidencethatalteredperipheralbloodNKanduterineNKcellsarerelatedtorecurrentmiscarriage

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Infec>ons

•  Bacterialvaginosisinthe1stTMisariskfactorfor2ndTMmiscarriageandPTD:oralclindamycinsignificantlyreducesrisk

•  Noroleforrou>neTORCHinves>ga>ons•  Noroleofan>bio>ctherapyinwomenwithaprevious2ndTMmiscarriage•  Anysevereinfec>onthatleadstobacteraemiaorviraemiacancausesporadic

miscarriage•  Syphilisinareasofhighprevalence

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Thrombophilias

•  Associa>onbetweenthrombophiliaandlatepregnancylosshasbeenconsistently

strongerthanforearlypregnancyloss

•  Womenwith2ndTMmiscarriageshouldbescreenedforinheritedthrombophilias

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Thrombophilias:Tests

•  FactorVLeiden•  Ac>vatedproteinCresistance•  Prothrombingenemuta>on•  ProteinCandpro>enSdeficiency•  Methylenetetrahydrofolatemuta>on(MTHFR)•  CarriersoffactorVLeidenorprothrombingenemuta>onhavedoubletheriskof

experiencingrecurrentmiscarriagecomparedwithwomenwithoutthesethrombophilicmuta>ons

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LutealPhaseDefect

•  ControversialcauseofRPL•  NoconvincingstudiesshowingLPDtreatment

improvespregnancyoutcome(LeeSeminReprodMed2000;18(4):433-40)

•  80%ofwomenwithlowmid-lutealprogesteroneproceedtoterm

•  20%offer>lewomenhaveabnormalendometrialbiopsies

•  Progesteroneand/orovula>oninduc>onforLPD

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Malefactor

•  Nosignificantdifferenceinsemenparameters•  Nodifferenceinincidenceofan>-sperman>bodies•  Asidefromcytogene>cabnormali>es,malefactorcontribu>ontoRPLunknown

(HillASRM2002Course6p.56)•  Oligoasthenoteratospermia35-74%•  Fer>ledonorsperm4-7%

•  DNAFragmenta>onmayresultinearlyembryoloss(HumReprod.2006Nov;21(11):2876-81)

()

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EnvironmentalFactors

Confirmedassocia>on•  Ionizingirradia>on•  Organicsolvents•  Alcohol•  Mercury•  Lead

(Gardella&HillSeminReprodMed2000;18(4):407-424)

Suspectedassocia>on•  Caffeine(>300mg/d)

•  Fever•  Cigare`eSmoking

•  Unknownassocia>on•  Pes>cides

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Summary:tests

•  FBC:Plateletcount•  APLan>bodies•  Thrombophiliascreen•  FSH,LH,Day21progesterone,Prolac>n•  Parentalkaryotypes•  HVSandChlamydia•  TFT,Thyroidan>bodies•  TestsforPCOS,DMifindicated•  USS•  Hysteroscopy

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Summary

•  Morethan50%ofcoupleswithRPLhavenoexplana>ondespiteextensiveevalua>on

•  Roleofaspirin,progesteronesupplements

•  70%livebirthratesreportedincoupleswithunexplainedRPLwhoundertakeanuntreatedsubsequentpregnancy

•  dependsonmaternalage&numberofpriorlosses

•  Informa>veandsympathe>ccounselingappearstoplayanimportantrole

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Recurrent miscarriage package from London Gynaecology

•  Ourrecurrentmiscarriagepackageaimstoquicklydiagnosereasonsformiscarriageinwomen•  30minuteconsulta>onwithaconsultantgynaecologist•  Abdominalandpelvicexamina>on•  Bloodtestsincluding•  Fullbloodcount•  Coagula>onprofile•  An>thrombinIII•  FactorVLeidengene•  FactorIIProthrombingene•  MTHFYgene•  Ac>vatedproteinCresistance•  Lupusan>coagulant•  ProteinCandProteinS•  An>cardioplipinan>bodies•  Chromosomalanalysis •  ComprehensivereporttoyouandyourGP•  Directaccesstoconsultant24/7

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ThankYou London Gynaecology Limited The Portland Hospital 212, Great Portland Street London W1W 5QN Practice Manager: Viviana Amoretti M: 07971 200 832 T : 020 8367 8999 F : 020 8082 5667 [email protected] www.london-gynaecology.com